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Abstract

Backgrounds: Hypertrophic Cardiomyopathy (HCM) is a popular inherited disease which leads to heart failure, arrhythmia and sudden cardiac death. Although several genetic mutations causing HCM have been identified, disease mechanism has not been fully understood yet. Therefore, we tried to identify the disease mechanism of HCM using HCM patient-specific iPSCs.

Methods and Results: We generated patient-specific iPSC-CMs from members in families carrying a HCM causing missense mutation (Glu927Lys) in MYH7 gene and have analyzed the phenotype of these iPSC-CMs. All HCM-iPSC lines have normal morphological characteristics and express pluripotency-related genes comparable to ES cells and normal iPSCs. There were no significant differences between established iPSC lines in terms of the differentiation propensity into cardiomyocytes. In comparing the phenotype of iPSC-CMs after 1-month culture without any stimuli, the ratio of disorganized sarcomeric CMs were significantly higher in the case of HCM patients than in the case of healthy persons (30.2% versus 13.3%; p<0.05).In terms of the cell size, HCM patients-derived iPSC-CMs tended to be larger than healthy persons-derived iPSC-CMs without statistically significance (cell size; 2999um2 versus 2573um2, p=0.06). Additionally, the ratio of multinucleated CMs and Ki67 positive CMs were also significantly higher in HCM than in healthy persons (multinucleated CMs: 12.9% versus 7.3%; p<0.05, Ki67-positive CMs; 29.8% versus 16.6%, p<0.05). These results suggested that cell cycle activation without environmental factors would be one of the processes of CMs hypertrophy in HCM patients.

Conclusions: HCM patients-derived iPSC-CMs showed some parts of disease phenotype and cell cycle activation ahead of apparent CMs hypertrophy. These HCM disease model using patient-specific iPSCs would be useful for identification of new insights of HCM. Further detailed experiments will be necessary to fully understand the disease mechanism of HCM.